This award will enable the applicant to obtain training in postnatal dental pulp stem cell-based regenerative medicine, with an emphasis on tissue-engineering the pulp-dentin complex. The PI will expand his scientific skills into this new research area of regenerative endodontics through a proposed intercollegiate program that involves training in the laboratories of well-known researchers. The overall objective of the proposed research is to develop regenerative dental (endodontics) approaches with biomaterials as the PI progresses into research independence. The central hypothesis of the proposed research is that a natural hydrogel-based biomatrix, seeded with an enriched population of dental pulp-derived odontoblast stem cells/progenitors, will promote regeneration of dental pulp tissue and deposition of a reparative dentin barrier to maintain tooth vitality. The literature suggests that ~4 million root canal procedures are performed annually in the US. Thus, novel therapeutic intervention is needed to promote rapid healing of dental pulp tissue and the production of a new dentin barrier for regeneration of the dental pulp, so that conventional root canal therapy (involving removal of pulp tissue in whole and preparation of root dentin) or permanent tooth extraction can be avoided. Such therapy will enable tooth retention and reduce dental care costs associated with more drastic measures. The specific aims of the proposed research are (1) identification of the biological responses of the dentin-pulp complex to stress conditions, thereby obtaining parameters for a novel method to enrich progenitor cells for repair of dental pulp tissue;(2) synthesis of hyaluronic acid analogues that include progenitor pulp cells to promote their proliferation, differentiation, and biomineralization;and (3) determination of the ability of enriched dental pulp stem cells delivered in a biomimetic hydrogel composite to regenerate the pulp-dentin complex. This interdisciplinary research program will involve mentors and co-mentors from the areas of cel biology, molecular genetics, bioengineering, and materials science, along with an advisory committee of senior medical scientists, to provide guidance to the PI. Training will be focused at the University of Illinois at Chicago (UIC) College of Dentistry, the UIC College of Medicine, and the Bioengineering Program, representing a cadre of scientists with the expertise needed for the proposed training. Experts in (a) cellular interactions with hyaluronic acid for treatment modalities, (b) tisue engineering and regenerative medicine, (c) molecular mechanisms and gene function in tooth development, (d) dental pulp stem cells and mesenchymal stem cells, and (e) dentin matrix proteins involved in biomineralization will ensure the PI's success as an independent scientist to develop the advanced dental restorative therapeutic modality. PUBLIC HEALTH RELEVANCE: The proposed research will lead to development of a novel endodontic technique to regenerate dental pulp tissue and form reparative dentin, using a special biological substrate for proliferation and differentiation of progenitor pulp stem cells/mesenchymal stem cells to tissue-engineer the pulp-dentin complex. Ideally, the new material will also provide novel treatment of root formation in immature permanent dentition, and have uses in other maxillofacial structures.